RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

Ruthenium complexes are attracting increasing attention as second-generation metal-based anticancer agents, with NAMI-A and KP1019 as the major representatives of this class having undergone clinical trials. Our recent interest has been focused on the synthesis and characterization of new amphiphilic derivatives of nucleosides (nucleolipids). These compounds have been selected as core scaffolds linked to RuIII complexes and capable of self-assembly into stable nanostructures in aq. solutions so to transport the metal ions efficiently into the cell. Through the use of ribo- and deoxyribonucleosides as starting building blocks, a mini-library of nucleolipidic RuIII complexes decorated with diverse hydrophilic and lipophilic chains and incorporating the NAMI-A analogue AziRu has been prepared. When co-aggregated with biocompatible lipids, these RuIII-containing nucleolipids proved to be stable for months under physiological conditions. Detailed microstructural characterization, carried out by a combined approach including different physico-chemical techniques, allowed their stability, size and shape to be determined. Tested on a panel of human and non-human cells, all of the studied RuIII complexes showed potent in vitro anticancer activity, significantly higher than that of NAMI-A-like analogues, and minimal toxicity. Here we summarize the design and synthetic procedures developed to prepare these new Ru-containing candidate drugs, discussing the beneficial effects achievable through exploiting nucleolipid appendages in the delivery of metal-based drugs.